Discovery of novel, orally active dual NK1/NK2 antagonists

Exploration of the SAR around selective NK2 antagonists, SR48968 and ZD7944, led to the discovery that naphth-1-amide analogues provide potent dual NK1 and NK2 antagonists. ZD6021 inhibited binding of [3H]-NKA or [3H]-SP to human NK1 and NK2 receptors, with high-affinity (Ki=0.12 and 0.62nM, respectively). In functional assays ZD6021 had, at 10−7M, in human pulmonary artery pKB=8.9 and in human bronchus pKB=7.3, for NK1 and NK2, respectively. Oral administration of ZD6021 to guinea pigs dose-dependently attenuated ASMSP induced extravasation of plasma proteins, ED50=0.5mg/kg, and NK2 mediated bronchoconstriction, ED50=13mg/kg.